期刊
ONCOIMMUNOLOGY
卷 7, 期 12, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2018.1502130
关键词
Sphk1; ccRCC; Sunitinib resistance; FTY720; array
资金
- Advanced technology promotion project of Shanghai Municipal Commission of Health and Family Planning [27 HYR 2013]
Sphingosine kinase 1 (SphK1) is the major source of the bioactive lipid and GPCR agonist sphingosine 1-phosphate (S1P). Although alterations in SphK1 expression and activity have been detected in various human malignancies, its potential molecular mechanisms in the development and sunitinib resistance of clear cell renal cell carcinoma (ccRCC) remain obscure. In this study, we aim to evaluate the clinical significance of SphK1 and to explore the therapeutic implications of combination approach for ccRCC patients. We identify upregulation of SphK1 significantly associated with poor prognosis of large cohort of ccRCC patients, which contributing to cell proliferation, colony formation, migration and survival. Suppression of SphK1 activity either by shRNA or pharmacologic inhibitior FTY720 suppresses cell growth in vitro and in vivo. A comprehensive phosphoprotein antibody array reveals that SphK1 overexpression promoted RCC progression by regulating the Akt/mTOR pathway. Moreover, FTY720 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that increased SphK1 kinase activation defines an important mechanism for sunitinib resistance, therefore contributes to tumour development and represents therapeutic targets for ccRCC.
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